It has been estimated that the human intestine harbours 1013 to 1014 bacterial cells and the number of bacteria outnumbers the total number of cells in the body by a factor of 10 (Gill et al. Science 312, 1355 (2006)). The microbiota of the human intestine is a complex and very dynamic microbial ecosystem, which is considered to serve numerous important functions for its human host, including protection against pathogens, induction of immune regulatory functions, nutrient processing and metabolic functions (Tojo World J. Gastroenterol. 20, 15163 (2014)). The intestinal microbiota consists of various populations, which are important to preserve human health, and recent research has been able to link imbalances in the intestinal bacterial population to both intestinal and extra-intestinal inflammatory diseases (Buie Clin. Ther. 37, 976 (2015); Fung et al. Curr. Allergy Asthma Rep. 12, 511 (2012); Ley et al. Nature 444, 1022 (2006); Larsen et al. PLoS One 5, e9085 (2010)).
Bifidobacteria are considered one of the most beneficial probiotics, and strains of B. adolescentis have been widely studied for their effects against specific pathogens. The mechanisms behind the protecting effect include enhancement of the host's immune system and suppression of pathogenic gene expression. A study has recently shown that B. adolescentis can protect mice from infection by Yersinia enterocolitica by modulating the host intestinal immune system by increasing plasmacytoid dendritic cell and regulatory T-cell frequencies (Wttmann et al PLoS One 8, e71338 (2013)). In line with this, an in vitro study has shown that B. adolescentis can attenuate pathogen-triggered inflammation by inhibiting IL-8 cell secretion induced by Salmonella Typhimurium DT104 (Carey et al. Can. J. Microbiol. 59, 9 (2013)). B. adolescentis has also been found to have antiviral activity through suppression of viral gene expression (Cha et al. BMC Med. 10:72 (2012); Kim et al. Biotechnol. Biotechnol. Equip. 28, 681 (2014)). Metabolic end products such as short chain fatty acids (acetate, propionate and butyrate), produced during carbohydrate fermentation, also contribute to intestinal functionality and probiotic attributes of bifidobacteria. It has previously been shown that acetate produced by bifidobacteria can enhance intestinal defence mediated by epithelial cells and thereby protect the host against assault (Fukuda et al. Nature 469, 543 (2011)). In addition, while bifidobacteria do not produce butyrate as an end product of fermentation, the importance of metabolic cross-feeding on acetate by butyrate-producing bacteria in the gut has been demonstrated (Belenguer et al Appl. Environ. Microbiol. 72, 3593 (2006); Duncan et al. Int. J. Obes. 32, 1720 (2008)). Butyrate is the primary energy source for colonocytes and has been reported to regulate the physical and functional integrity of the normal colonic mucosa by altering mucin gene expression (Shimotoyodome et al. Comp. Biochem. Physiol. A, Mol. Integr. Physiol. 125, 525 (2000); Blottière et al. Proc. Nutr. Soc. 62, 101 (2003). The increase of mucin protein induced by butyrate, has recently shown to elevate adherence of B. adolescentis, which subsequently reduced the adherent ability of E. coli (Jung et al. Nutr. Res. Pract. 9, 343 (2015)).
Obesity, the major risk factor for type 2 diabetes, is associated with changes in gut microbiota composition. An altered gut microbiota has the potential to affect host metabolism and energy storage and to affect gut permeability, and as a consequence, increase plasma lipopolysaccharides (LPS) and give rise to metabolic endotoxemia and insulin resistance (Cani et al. Gut Microbes 3, 279 (2012)). Lower levels of bifidobacteria have previously been detected in obese versus lean and diabetic versus non-diabetic individuals (Duncan et al. Int. J. Obes. 32, 1720 (2008); Schwiertz et al. Obesity 18, 190 (2010)). B. adolescentis in particular has been observed to be underrepresented in type 2 diabetic patients compared to controls (Lê et al. Front. Physiol. 1 (2013)). Studies have shown that B. adolescentis can reduce intestinal permeability (Wu et al. Dig. Dis. Sci. 55, 2814 (2010)), and can ameliorate visceral fat accumulation and insulin sensitivity (Chen et al. Br. J. Nutr. 107, 1429 (2012)), hence inhibiting the pathological conditions of obesity. Further, B. pseudocatenulatum, a member of the B. adolescentis phylogenetic group, has been shown to ameliorate both metabolic and immunological dysfunctions related to obesity in a mouse model for obesity (Cano et al. Obesity. 21, 2310 (2013)).
The microbial composition has also been suggested to play a role in the pathophysiology of intestinal diseases such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) (Qin et al. Nature 464, 59 (2010); Talley et al. Lancet 360, 555 (2002)). Alterations in intestinal microbial composition in both IBD and IBS patients have been reported, and studies have revealed a lower number of bifidobacteria in both IBS and IBD compared to healthy subject (Sokol et al. Inflamm. Bowel Dis. 15, 1183 (2009); Mylonaki et al. Inflamm. Bowel Dis. 11, 481 (2005); Kerckhoffs et al. World J. Gastroenterol. 15, 2887 (2009); Casén et al. Aliment. Pharmacol. Ther. 42, 71 (2015)). Dysbiosis has recently been established in IBD by characterization of five species including decreased abundance of B. adolescentis (Joossens et al. Gut 60, 631 (2011)). Certain Bifidobacterium species, including B. adolescentis, have been reported to provide benefits against conditions like IBD and IBS (Whorwell et al. Am. J. Gastroenterol. 101, 1581 (2006); Guyonnet et al. Aliment. Pharmacol. Ther. 26, 475 (2007); Chen et al. World J. Gastroenterol. 15, 321 (2009); Frick et al. Infect. Immun. 75, 3490 (2007)); one mode of action could be the immunomodulatory capacity of these species, acting as IL-10 inducer enhancing an anti-inflammatory immune response (Pozo-Rubio et al. Br. J. Nutr. 106, 1216 (2011); Hoarau et al. J. Allergy Clin. Immunol. 117, 696 (2006)).
Selective stimulation of specific intestinal bacteria to promote their growth and metabolic activity could be a helpful approach in creating a benign intestinal microbial community. Because some bacteria are able to produce a large selection of carbohydrate active enzymes (such as glycoside-hydrolases and transporters), the bacteria can grow on carbon sources, which may be less easily used by other members of the intestinal microbial community.
Human milk oligosaccharides (HMOs) are a heterogeneous mixture of soluble glycans found in human milk. They are the third most abundant solid component after lactose and lipids in human milk and are present in concentrations of 5-25 g/l (Bode: Human milk oligosaccharides and their beneficial effects. In: Handbook of dietary and nutritional aspects of human breast milk (Zibadi et al. (eds.)) pp. 515-32, Wageningen Academic Publishers (2013); Gabrielli et al. Pediatrics 128, e1520 (2011)). HMOs are resistant to enzymatic hydrolysis in the small intestine and are thus largely undigested and unabsorbed (Gnoth et al. J. Nutr. 130, 3014 (2000); Engfer et al. Am. J. Clin. Nutr. 71,1589 (2000); Brand-Miller et al. P. Nutr. Soc. Australia 19, 44 (1995)). The majority of HMOs that reach the colon serve as substrates to shape the gut ecosystem by selectively stimulating the growth of specific bacteria. HMOs are believed to substantially modulate the infant gut microbiota and play a decisive role in the differences in the microbiota of formula-fed and breast-fed infants. These differences include the predominance of bifidobacterium in the gut of breast-fed infants compared to a more diverse gut microbiota in formula-fed infants (Sela et al. Trends Microbiol. 18, 298 (2010); Bezirtzoglou et al Anaerobe 17, 478 (2011)). This is viewed as beneficial for the infant because strains of bifidobacterium species are believed to have a positive effect on gut health (Chichlowski et al. J. Pediatr. Gastroenterol. Nutr. 55, 123 (2012); Fukuda et al. Nature 469, 543 (2011); Peran et al. J. Appl. Microbiol. 103, 836 (2007)). However, it is not known if HMOs can stimulate the growth of bifidobacteria in the adult human intestine.
However, it is unclear how to effectively increase the abundance, particularly the relative abundance, of bifidobacteria, in particular a Bifidobacterium of the B. adolescentis phylogenetic group, especially B. adolescentis and/or B. pseudocatenulatum, in human microbiota. Genomic analyses of strains of B. adolescentis indicate that B. adolescentis has a nutrient acquisition strategy targeting plant-derived glycans, in particular starch and starch-like carbohydrates (Duranti et al. Appl. Environ. Microbiol. 80, 6080 (2014)). This fits with its increased abundance in older children and adolescence as the diet increasingly includes starches. However, many organisms in the gastro-intestinal tract target plant-derived glycans such as starch. Hence, feeding starches will not preferentially increase the abundance of B. adolescentis and/or B. pseudocatenulatum but rather will increase all the organisms able to metabolise starch. It may also be possible to administer B. adolescentis and/or B. pseudocatenulatum strains as probiotics. However, the long term viability of B. adolescentis and/or B. pseudocatenulatum strains in the gastro-intestinal tract is unclear. In in vitro tests, B. adolescentis generally shows no ability to grow in breast milk and utilise human milk oligosaccharides (Wittmann et al. PLoS One 8, e71338 (2013)), unlike B. infantis, B. bifidum and B. breve species. This is corroborated by the low relative absence of B. adolescentis in the infant intestinal tract.